tbuckley/cabot-search huggingface dataset:
Preoperative chemoradiotherapy with capecitabine with or without temozolomide in patients with locally advanced rectal cancer: A prospective, randomized phase 2 study stratified by MGMT (O<sup>6</sup>-methylguanine DNA methyltransferase) status: KCSG-CO17-02.
Authors: Chung Ryul Oh, Jae Ho Jeong, Ji Sung Lee, Jeong Eun Kim, Sun Young Kim, Tae Won Kim, Jene Choi, Jihun Kim, In Ja Park, Seok-Byung Lim, Jin-hong Park, Jong Hoon Kim, Moon Ki Choi, Yongjun Cha, Ji Yeon Baek, Seung-Hoon Beom, Yong Sang Hong
Journal: Journal of Clinical Oncology (2022)

3605 Background: We aimed to evaluate the clinical efficacy of adding temozolomide (TMZ) to preoperative capecitabine (CAP)-based chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC) and validate O 6 -methylguanine DNA methyltransferase (MGMT) methylation status as a predictive marker for TMZ combined regimens. Methods: : LARC patients with clinical stage II (cT3-4N0) or III (cT any N+) disease were enrolled. They were stratified into MGMT unmethylated (uMGMT) and MGMT methylated (mMGMT) groups by methylation-specific PCR before randomization, and then were randomly assigned (1:1) to one of four treatment arms: uMGMT/CAP (arm A), uMGMT/TMZ+CAP (arm B), mMGMT/CAP (arm C), and mMGMT/TMZ+CAP (arm D). The primary endpoint was the pathologic complete response (pCR) rate. Results: Between November 2017 and July 2020, 64 patients were randomized. Slow accrual caused early study termination. After excluding 4 ineligible patients, 60 were included in the full analysis set. The pCR rate was 15.0% (9/60), 0%, 14.3%, 18.8%, and 26.7% for arms A, B, C, and D, respectively ( p= 0.0498 between arms A and D). The pCR rate was 9.7% in the CAP group (arms A+C), 20.7% in the TMZ+CAP group (arms B+D), 6.9% in the uMGMT group (arms A+B), and 22.6% in the mMGMT group (arms C+D). Grade 1–2 nausea or vomiting was significantly more frequent in the TMZ+CAP treatment groups (arms B+D) than in the CAP treatment groups (arms A+C, p&lt; 0.001) with no difference in grade 3 adverse events (AEs). There were no grade 4 or 5 AEs. Conclusions: The addition of TMZ to CAP-based CRT tended to improve pCR rates, particularly in those with mMGMT LARC. MGMT status may warrant further investigation as a predictive biomarker for chemotherapeutic agents and radiotherapy. Clinical trial information: NCT03156036.
Prevalence, symptom management, and reporting of cannabis use among invasive cancer patients.
Authors: Theodore M Brasky, Alison M Newton, Sara Conroy, Anita Adib, Neema C Adley, Scott A Strassels, John L. Hays, Ziva D Cooper, Theodore L Wagener, Jessica L. Krok-Schoen
Journal: Journal of Clinical Oncology (2022)

e24114 Background: Interest in the use of cannabis-based products, including marijuana (products containing ≥0.3% tetrahydrocannabinol [THC]) and cannabidiol (CBD; containing &lt; 0.3% THC) for cancer symptom management, is increasing. Preliminary studies suggest that marijuana and CBD products are effective in alleviating common cancer- or treatment-related symptoms. Few studies have reported on the magnitude of cannabis use among cancer patients, but data remain limited to states with legalized non-medical (i.e., recreational) use. Further, none have assessed the prevalence of CBD use in cancer patients. The reasons for cannabis-based product use and patient attitudes towards discussing use with their physicians are not well understood. Methods: We report preliminary results from an ongoing anonymous cross-sectional study of cannabis use among patients attending 8 clinics at the Ohio State University Comprehensive Cancer Center. Eligible patients were diagnosed with invasive cancer and treated in the past 12 months. Between July 2021 and January 2022, 771 patients were contacted and 639 (82.9%) agreed to participate. Participants answered a validated, extensive cannabis-focused questionnaire and were remunerated with a gift card. We report here frequencies and prevalence proportions of cannabis-based product use, and cannabis-related behaviors and attitudes on reporting use with cancer providers. Missing values were included in the denominator of prevalence calculations, thereby making estimates conservative. Results: Participants were equally distributed by sex, White (86.4%), and resided within Ohio (90.3%). Among 433 patients who reported age, the median was 47 years (IQR 38-53). The prevalence of current cannabis-based product use was 15.2% (97/639), with overall prevalence of 6.9% for exclusive marijuana use, 1.7% exclusive CBD use, and 5.2% poly-use. Among current users, patients primarily reported inhaling or ingesting cannabis products; fewer reported topical or other applications. The top 5 reported reasons for cannabis use were to treat stress, improve sleep, reduce pain, improve appetite, and to treat depression. Among current users, 66% reported that their cancer care team was aware of their cannabis use, 17.5% reported none of their healthcare providers were aware, and 15.4% reported a medical professional unaffiliated with their cancer care was aware. A large proportion (86.6%) felt comfortable discussing cannabis with their treating physician. Conclusions: Our results indicate current cannabis-based product use for symptom relief among a sizeable minority of adults with cancer in a state where only medicinal marijuana is legalized. Further research is needed to characterize provider perspectives and communication about reported cannabis use among their patients.
EDEM2 regulation of cardiac lipid metabolism in heart failure with preserved ejection fraction
Authors: R Raja, W Liu
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Background Heart failure with preserved ejection fraction (HFpEF) is the most predominant form of heart failure (HF) worldwide, one which confers substantial mortality and has no efficacious treatments. Lipid mishandling greatly contributes to the pathophysiology of HFpEF, nevertheless, the key mechanistic features regulating cardiac lipid overload remain poorly understood. EDEM2 plays a crucial role in the ER-associated degradation (ERAD) pathway. Recent studies show that ERAD-associated proteins are implicated in cellular lipid homeostasis, however, the role of EDEM2 is cardiac lipid metabolism remains poorly understood. Here, we investigate the mechanisms by which EDEM2 regulates cardiomyocyte lipid metabolism and cardiac dysfunction in HFpEF. Methods In vivo two-hit disease model of HFpEF, Adeno-associated virus serotype 9 (AAV9)-mediated cardiac-specific gene overexpression, tail-cuff blood pressure recordings, echocardiography, histology and qPCR. Results Under HFpEF inducing conditions, AAV9-Gfp injected mice (as controls) displayed an increased E/A ratio and IVRT both of which are indicative of diastolic dysfunction. Conversely, cardiac-specific EDEM2 overexpression prevented diastolic dysfunction in mice subjected to HFpEF conditions. Systolic function remained unchanged between groups. Interestingly, EDEM2 overexpression reduced myocardial neutral lipid accumulation and prevented severe oxidative stress and cardiac pathological remodeling. More importantly, although genes participating in fatty acid uptake and lipid droplets synthesis in the heart were comparable between AAV9-Gfp and AAV9-EDEM2 groups, those involved in lipolysis and fatty acid oxidation were upregulated in mice with cardiac-specific EDEM2 overexpression. Conclusion Cardiomyocyte-specific EDEM2 overexpression mitigates myocardial steatosis in a two-hit murine model of HFpEF, likely through enhancing fatty acid utilisation in the myocardium.
Assessment of a HER-2 scoring system and its correlation of HER2-targeting antibody-drug conjugate therapy in urothelial carcinoma.
Authors: Huizi Lei, Yun Ling, Pei Yuan, Jun Guo, Xinan Sheng, Ai-Ping Zhou, Jianming Ying
Journal: Journal of Clinical Oncology (2022)

4572 Background: Human epidermal growth factor receptor 2 (HER2) overexpression is related to many tumor treatments. RC48-ADC, a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E, has shown a promising efficacy in patients with HER2-positive locally advanced or metastatic urothelial carcinoma (mUC). The characteristic expression and scoring systems of HER2 have existed in breast cancer, gastric cancer for many years, but not in UC. We aimed to explore the expression pattern of HER2 in UC and develop a validated HER2 scoring system. Methods: A total of 137 patients and 43 patients in two studies of cohort 1 and cohort 2 were enrolled, respectively. The patients of the cohort 2 were enrolled in the open-label, multicenter, phase II study of RC48-ADC. Formalin-fixed paraffin-embedded urothelial cancer samples were tested for HER2 status using the fluorescence in situ hybridization (FISH) PathVysion HER2 DNA probe kit (PathVysion, Abbott Molecular, USA). Immunohistochemistry (IHC) was performed using the Ventana Benchmark XT (Ventana Medical Systems, USA). The 2018 ASCO/CAP HER2 scoring system of breast cancer was adopted and modified to score HER2 expression level in UC. Results: The expression rate of HER2 (IHC 2+/3+) was 24.1% (33/137). In HER2 IHC status 3+ or 2+ patients, the HER2 amplified rate was 31% (13/42). The objective response rates in RC48-ADC treatment patients with IHC 3+, IHC 2+ and FISH +, IHC 2+ and FISH - were 58.8%, 66.7% and 40%, respectively. Heterogeneity of HER2 protein expression was 55.5% (15/27) and the objective response rate had no significant difference between patients with tumor heterogeneity and homogeneity. Conclusions: The modified HER2 testing scoring system could be applied to UC to determine which patient might benefit from anti-HER2-ADC treatment. There was a trend towards a better benefit for patients with HER2 amplification and the tumor heterogeneity did not influence the drug efficacy.
SURG-16. Pediatric oncology neurosurgery, four years after centralization in the Princess Máxima Center
Authors: Kirsten van Baarsen, Mariam Slot, Peter Woerdeman, Sen Han, Eelco Hoving
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: In 2018, the Princess Máxima Center officially opened its doors as a national referral center for pediatric oncology in the Netherlands. This centralization of pediatric oncology also reshaped the pediatric neurosurgery landscape. Almost four years after centralization it is time to make up the balance. METHODS: From the start in May 2018, a predesigned database was kept for all neurosurgical procedures performed in the Princess Máxima Center, Utrecht. Data was collected by a well-trained medical student and under close supervision of a pediatric neurosurgeon. Patient demographic data, tumor data (location, pathology), surgical data (approach, intended and obtained extent of resection), radiology data, and follow up data (complications, functional outcome) were collected. PRELIMINARY RESULTS: From May 2018 to December 2021, 783 oncology related surgeries have been performed in 472 individual patients (56% male; mean age 8 years). There were 316 cranial tumor resections, 279 of which were first resections. Pilocytic astrocytoma was the most frequent diagnosis (38%), followed by medulloblastoma (14%) and ependymoma (11%). Among the more rare tumors there were 29 diffuse midline gliomas and 29 craniopharyngiomas, reflecting the high volume after centralization. The extent of tumor resection and Clavien Dindo complication grading are correlated to time after centralization. CONCLUSION: Four years after the start of centralization, the pediatric oncology neurosurgery service in the Netherlands is well established. Clustering has resulted in high absolute numbers, even for rare tumor types, and growing experience. With this series we hope to create an international benchmark for pediatric oncology neurosurgery.
Retraction: Targeting KDM6A Suppresses SREBP1c-Dependent Lipid Metabolism and Prostate Tumorigenesis
Authors: Donge Tang, Yong Dai, Songhui Xu
Journal: Cancer Research (2022)

This article (1) has been retracted at the request of the editors. Following an internal review, it was determined that authorship of the original article is disputed. Eight individuals who attest that they were unaware of the submitted manuscript and did not agree to their authorship were removed as authors in a prior Correction (2).A copy of this Retraction Notice was sent to the last known email addresses for the three remaining authors. One author (Songhui Xu) did not agree to the retraction; two authors (Donge Tang, Yong Dai) did not respond.
Smoldering multiple myeloma progression to multiple myeloma in a community-based population.
Authors: Raleigh Ayoolu Fatoki, Diane M. Carpenter, Nirmala D. Ramalingam, Adnan Ahmed Khan, Bijay P. Nair, Ryan Lloyd Stevenson, Michael M. Green, Joan C. Lo, David M. Baer
Journal: Journal of Clinical Oncology (2022)

e20015 Background: Few studies have characterized patients with smoldering multiple myeloma (SMM) in ethnically diverse settings and data regarding progression to multiple myeloma (MM) in real-world clinical populations is limited. Using data from a large healthcare system, we examined a contemporary cohort of adults with confirmed SMM and their progression to MM. Methods: We conducted a retrospective cohort study of SMM cases from 2010-2017 in Kaiser Permanente Northern California (KPNC). We used the KPNC SEER-based Cancer Registry to identify potential SMM cases by ascertaining MM cases with either: 1) “asymptomatic, evolving, or smoldering myeloma” status in the Cancer Registry or 2) mention of “smoldering” in clinical records. Chart review was conducted for potential SMM cases and confirmed SMM status was assigned using the 2014 IMWG criteria. SMM cases were followed for progression to MM and myeloma-directed therapy, excluding those with KPNC membership &lt;1 year after diagnosis. Time to MM progression (or treatment) was examined. SMM cases were classified during follow-up as: a) SMM, no progression to MM (and no receipt of myeloma-directed therapy); b) SMM, progression to MM (and receipt of myeloma-directed therapy); and c) SMM, receipt of myeloma-directed therapy without frank progression to MM (follow-up was censored at treatment). Results: During 2010-2017, we identified 152 adults with confirmed SMM. The median age at diagnosis was 71 years (IQR, 62-78), 56% were male, and 55% were non-Hispanic White, 17% Black, 9% Hispanic, and 18% Asian. During follow-up, 28% of patients progressed to MM, with a median time to progression of 1.2 years (IQR 0.8-2.0). Over half (58%) did not progress during a median follow-up time of 3.4 years, and an additional 14% received treatment before a MM-defining event. Progression data by demographic group is shown in Table. Conclusions: This is one of the first studies to examine SMM progression in an ethnically diverse cohort using the 2014 IMWG criteria. Although follow-up time was limited, we found that over half of the identified SMM cases did not progress to MM. However, patients who did progress to MM generally required treatment within 2 years of SMM diagnosis. These findings support efforts to identify high-risk patients with SMM who may benefit from early initiation of therapy. [Table: see text]
Longitudinal variation in SARS-CoV-2 antibody levels and emergence of viral variants: a serological analysis
Authors: Frauke Muecksch, Helen Wise, Kate Templeton, Becky Batchelor, Maria Squires, Kirsty McCance, Lisa Jarvis, Kristen Malloy, Elizabeth Furrie, Claire Richardson, Jacqueline MacGuire, Ian Godber, Alana Burns, Sally Mavin, Fengwen Zhang, Fabian Schmidt, Paul D Bieniasz, Sara Jenks, Theodora Hatziioannou
Journal: The Lancet Microbe (2022)

Serological assays are being used to monitor antibody responses in individuals who had SARS-CoV-2 infection and those who received a COVID-19 vaccine. We aimed to determine whether such assays can predict neutralising antibody titres as antibody levels wane and viral variants emerge.
Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis
Authors: Càndid Villanueva, Ferran Torres, Shiv Kumar Sarin, Hasnain Ali Shah, Dhiraj Tripathi, Anna Brujats, Susana G. Rodrigues, Ankit Bhardwaj, Zahid Azam, Peter C. Hayes, Ankur Jindal, Shahab Abid, Edilmar Alvarado, Jaume Bosch
Journal: Journal of Hepatology (2022)
Anlotinib in radioactive iodine-refractory differentiated thyroid cancer and the usefulness of SUVmax as an prognostic indicator.
Authors: Zongping Zhu, Jianyu Liu, Yueyun Ding, Dedao Shi, Feibo Zheng
Journal: Journal of Clinical Oncology (2022)

e18077 Background: Radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) is characterized by poor therapeutic effect on radioactive iodine with poor prognosis. Therefore, a variety of molecularly targeted drugs are used in the treatment of RAIR-DTC. However, sorafenib and lenvatinib are not “broad-spectrum” anti-cancer drugs for RAIR-DTC. The efficacy and safety of Anlotinib in the treatment of RAIR-DTC need to be studied. Methods: From September 2020 to September 2021, 9 patients with RAIR-DTC were included. Follow-up continued until disease progression or intolerable adverse events occurred. Efficacy was evaluated by serum triglycerides (Tg) and imaging (RECIST1.1). Adverse events were also recorded. Gender, age, maximum standard unit value (SUVmax), tumor metabolic volume (MTV), total glycolysis (TLG), pathological type and tumor stage were included in the univariate analysis. Results: 8 patients reached the standard of “partial biochemical remission”. The average Tg level of these 8 patients decreased by 74.8% after Anlotinib treatment. 15 target lesions (TLs) were found in 6 patients. The average reduction ratio of TLs in these 6 patients was 28.7%. Furthermore, we observed three (50%) PR, three (50%) SD, with an ORR of 50% and a DCR of 100% in these 6 patients. The severity of AEs in all 9 patients did not exceed Grade 2. The most common AEs were hand-foot skin reactions, diarrhea, and hypertension, which accounted for 5/9, 3/9, and 3/9, respectively. Serious drug-related AEs did not occur. The average decrease in Tg after 3 courses was significantly greater in the high metabolism group (TL SUVmax 27.9) compared with the average decrease in the low metabolism group (TL SUVmax &lt; 7.9), with 83.25% and 16.11% respectively (p = 0.027). There was no correlation between age, gender, pathological type, staging, other metabolic indexes of PET/CT and the ratio of patients' Tg reduction. Conclusions: Anlotinib can be used for the treatment of RAIR-DTC. This study confirmed the efficacy of Anlotinib with a high disease control rate. SUVmax can be used as an indicator to predict the therapeutic effect of Anlotinib in RAIR-DTC patients.
HGG-36. Elucidating the role of long non-coding RNAs in pediatric high grade gliomas
Authors: Jessica W Tsai, Frank P B Dubois, Dayle K Wang, Alexander Crane, Alexandra L Condurat, Brian Krug, Adam Brown, John G Doench, Nada Jabado, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Genomic and transcriptomic studies have elucidated new insights into the landscape of diffuse intrinsic pontine glioma (DIPG). However, the role of long non-coding RNAs (lncRNAs) has not been explored at depth in these tumors, and there have not been studies focused on how lncRNAs interact with the K27M histone mutation. In a recent analysis of nearly 200 DIPGs and pediatric high-grade gliomas (pHGG), we previously detected a novel, recurring structural variant in the lncRNA CCDC26. This rearrangement occurs in nearly 10% of all DIPGs, and we have furthermore identified alterations in more than 100 lncRNAs in DIPG. METHODS: To identify lncRNAs required for proliferation of patient-derived DIPG cancer cells, we designed two custom genome-scale lncRNA libraries. We generated a genome-scale lncRNA CRISPR-Cas9 knockout pooled library, consisting of 45,766 single guide RNAs (sgRNAs). Additionally, we generated a genome-wide CRISPR interference pooled library consisting of 45,608 sgRNAs, targeting lncRNA transcription start sites (TSS). RESULTS: We utilized in vitro histone-mutant pHGG models as well as edited clones of these models with the K27M mutant corrected in order to compare lncRNA dependencies in these two contexts. We have successfully performed genome-scale CRISPR-Cas9 knockout and CRISPR interference screens targeting lncRNAs in these cell lines, revealing lncRNA dependencies. Candidate dependencies in our CRISPR-Cas9 knockout screen include LOC100507412, LOC105379524, and LINC02193. CONCLUSION: Genome-wide lncRNA CRISPR knock-out and CRISPR interference screens are a novel approach for the unbiased identification of lncRNAs that are required for pediatric high-grade glioma proliferation. Further validation of specific lncRNAs is required, and these lncRNA dependencies represent potential novel therapeutic targets.
Access to technology to support telehealth in areas without specialty care for liver disease
Authors: Jacqueline B. Henson, Kara Wegermann, Yuval A. Patel, Julius M. Wilder, Andrew J. Muir
Journal: Hepatology (2022)

Telehealth may be a successful strategy to increase access to specialty care for liver disease, but whether the areas with low access to care and a high burden of liver-related mortality have the necessary technology access to support a video-based telehealth strategy to expand access to care is unknown.
MODL-14 Inhibition of cell cycle mechanisms to combat high-risk medulloblastoma
Authors: Katharina Bruckner, Lisa Mayr, Romana Sickha, Aniello Frederico, Sibylle Madlener, Lisa Gabler, Dominik Kirchhofer, Karl Roessler, Natalie Jäger, Walter Berger, Marcel Kool, Stefan M Pfister, Julia Schueler, Johannes Gojo, Daniela Lötsch-Gojo
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is the most common embryonal brain tumor in children, characterized by a high level of heterogeneity within this entity. Four major molecular groups have been defined - WNT, Sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4) - differing widely in genetic alterations and patient outcomes. Targeted treatment approaches are limited for high-risk MB including MYC-amplified G3, G4, or MYCN/GLI2-amplified SHH. Based on earlier studies describing the inhibition of cell cycle regulation as a therapeutic vulnerability in high-risk MB, we aimed to explore the efficacy and mode of action of approved CDK4/6 inhibitors in aggressive MB. First the in vitro sensitivity of pediatric G3 (n=5) MB cell models against palbociclib, ribociclib and abemaciclib was evaluated and compared to adult SHH (n=2) cells serving as MYC-negative controls. Abemaciclib most effectively reduced cell viability, exhibiting a mean IC50 value of 0.9 M in G3 compared to 2.1 M in SHH cells (p=0.007). Upon long-term exposure (7-10 days), again abemaciclib most potently decreased clonogenic survival already at 250nM in G3 MB cells. We observed a G1/S phase cell cycle arrest upon abemaciclib treatment and confirmed this by Western blot analyses, showing decreased Rb phosphorylation accompanied by reduced MAPK signaling. Interestingly, abemaciclib treatment distinctly reduced MYC protein and gene expression levels in MYC-amplified G3 cell models. In addition, exposure to abemaciclib decreased GLI2 and TERT mRNA levels, which was accompanied by induction of cellular senescence. Within the ITCC-P4 project, single mouse trials are currently being performed including abemaciclib treatment in orthotopic MB models. The detailed investigation of the precise mode of action in vitro and in vivo is ongoing. Summarizing, the CDK4/6 clinically approved inhibitor abemaciclib shows promising efficacy against high-risk MB in vitro.